Diazepinoisoquinolines

ABSTRACT

5-(Oxo, thio or imino)-7,8-dihydro(1,4)diazepino(7,1-a) isoquinolines, lower alkylenolethers, the N-oxide, quaternaries or salts thereof are neuroleptic agents.

United States Patent Gschwend Dec. 10, 1974 DIAZEPINO ISOQUINOLINES [56] References Cited [75] Inventor: Heinz Werner Gschwend, New UNITED STATES PATENTS Providence, NJ. 3,045,008 7/1962 Lombardino et al 260/2393 [73] Assignee: Ciba-Geigy Corporation, Ardsley, N.Y. Primary Examinerl-lenry R. Jiles Assistant ExaminerRobert T. Bond [22] Flled: 1972 Attorney, Agent, or FirmTheod0re O. Groeger; [21] Appl. No.: 221,053 Joseph G. Kolodny; John J. Maitner 52 us. Cl... 260/2393 T, 260/270 R, 260/283 R, [57] ABSTRACT 60/ R, 260/283 260/288 260/289 S-(Oxo, thio or imino)-7,8-dihydro[ l,4]diazepin0[7,l-

24/258 a] isoquinolines, lower alkylenolethers, the N-oxide, [51] Int.'Cl C07d 57/04 quaternaries or salts thereof are neuroleptic agents. [58] Field of Search 260/2393 T 4 Claims, No Drawings 1 DIAZEPINOISOQUINOLINES SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new -(oxo, thio or imino)-7,8-dihydro[ l ,4]diazepino[7,l-a]isoquinolines, preferably of those corresponding to Formula I wherein Ph is a l,2-phenylene group, each of R R and R is hydrogen or lower alkyl or R and R together are lower alkylene or alkenylene, R is hydrogen, lower alkyl, alkenyl, isoor heterocyclic aryl or aralkyl, X is oxo, thio or imino and alk is lower alkylene separating Ph from N by two carbon atoms, or of 5-lower alkylenolethers, the N-oxide, lower alkyl quaternaries or pharrnaceutically useful acid addition salts thereof, as well as of corresponding pharmaceutical compositions and methods for the preparation or application of said products, which are useful neuroleptic and anticonvulsive agents. I

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the above compounds of Formula I, the 1,2-

The lower alkylene group alk is preferably ethylene, but also 1,2-propylene, 1,2- or 2,3-butylene or -penty|- ene.

The compounds of the invention exhibitv valuable pharmacological properties. Primarily they show neuroleptic and anitconvulsive effects and cause a central adrenergic neuron blockade, particularly in the brain stem. This can be demonstrated in animal tests, using advantageously mammals, such as mice, rats or monkeys, as test objects. The compounds of the invention can be applied to the animals enterally or parenterally, e.g. orally or intraperitoneally, for example, in the form of aqueous solutions or starchy suspensions. The dosage may range between about 0.1 and 200 mg/kg/day, preferably between about 1 and 50 mg/kg/day. Having administered the compounds of the invention to the test animals, for example, up to 10 mg/kg/day p.o. to rats, they increase norepinephrine concentration in their brain stem and selectively decrease its turnover rate therein. When administered up to 50 mg/kg/day tric shocks taken by the animals increases with the dose phenylene group Ph is unsubstituted or substituted, by

one or more than one, preferably up to three, advantageously up to two, members selected from the group consisting of lower alkyl, e.g. methyl, ethyl, nor ipropyl or -butyl, free, etherified or esterified hydroxy, such as lower alkoxy, alkylenedioxy, aralkoxy, alkanoyloxy or halogeno, e.g. methoxy, ethoxy, nor ipropoxy or -butoxy; methylenedioxy, l,lor 1,2- ethylenedioxy or 2,2-propylenedioxy; benzyloxy; acetoxy, propionyloxy or pivalyloxy; fluoro, chloro or bromo; trifluoromethyl; or tert. amino, such as di-lower alkylamino, e.g. dimethylamino or diethylamino. The term lower, referred to above or hereinafter in connection with organic radicals or compounds respectively, defines such with up to seven, preferably up to four carbon atoms.

A lower alkyl group R R R or R is such illustrated above, but also tert. butyl, nor i-pe'ntyl,'-hexyl or -heptyl. A lower alkenyl group R is, for example, allyl or methallyl. A lower alkylene or alkenylene group R R, is preferably suchforming a three toseven membered Spiro-ring, e.g. ethylene, 1,2- or 1,3-propylene, 1,2-, 1,3-, 2,3- or 1,4-butylene, 1,4- or 1,5-pentylene or -hexylene; 1,4-but-2-enylene or l,5-pent-2-enylene.

An isocyclic aryl or aralkyl group is preferably that of the formula HPhC,,,H wherein Ph has the meaning given above and m is an integer from O to 4. A heterocyclic aryl or aralkyl group is preferably that of the formula Hc-C,,,H wherein m has the previous meaning and He is a pyridyl, fury] or thienyl group, either unsubstituted or substituted by up to three lower alkyl, preferably methyl groups, e.g. 2-, 3- or 4-(pyridyl or pyridylmethyl), 2- or 3-(furyl or furfuryl), 2- or 3- (thienyl or thenyl).

applied (Sidman procedure). For example, said effects can be observed with the 2-(3,4- methylenedioxyphenyl)-10,1 l-dimethoxy-7,8- dihydro[ l,4]diazepino[7, l -a]isoquinolin 5(4H)-onc, its hydrochloride or d,l-4-methyl derivative, characteristic compounds of the invention, down to a p.o. dose of-2.5 mg/kg/day in rats or 20 mg/kg/day p.o. in squirrel monkeys. Accordingly, the compounds of thein'ven tion are useful as neuroleptic and anticonvulsive agents, or as intermediates in the preparation of other valuable compositions of matter, especially of pharmacologically useful products.

Preferred compounds of the invention are those of Formula I, in which Ph is 1,2-phenylene (lower alkyl 1,2-phenylene, (hydroxy),,- l ,2-phenylene, (lower alkoxy),,- l ,2-phenylene, (lower alkylenedioxy )-l ,2- phenylene, (lower alkanoyloxy),,-l,2-phenylene, (halogeno),,-l ,2-phenylene, (trifluoromethyl )-l ,2- phenylene or (di-lower alkylamino)-1,2-phenylene, wherein n is an integer from 1 to 3, (preferably 1 or 2),

and R together are lower alkylene or alkenylene forming a three to seven membered Spiro-ring, R is hydro- 5 gen, lower alkyl, I-I'PhC,,,I'I or Hc-C,,,H wherein Ph has the meaning in'this paragraph, He is pyridyl, (lower alkyl),,-pyridyl, furyl, (lower alkyl),,- furyl, thienyl or (lower alkyl),,-thienyl, n is said integer from 1 to 3 and m is an integer from 0 to 4, X is oxo, thio or imino and alk is lower alkylene separating Ph from N by two carbon atoms, a S-lower alkylenolether, the N-oxide, lower alkyl quaternaries or pharmaceutically useful acid addition salts thereof, Outstanding are the compounds of Formula II wherein each of R and R is hydrogen, lower alkyl, lower alkoxy or halogen, or both R and R are lower alkylenedioxy, R is phenyl, (lower alkyl),,-phenyl, (lower alkoxy),,-phenyl, (lower alkylendioxy)-phenyl, (halogeno),,-phenyl, (trifluoromethyl)-phenyl, pyridyl, (lower alkyl),,-pyridyl, furyl, (lower alkyl),,-furyl, tienyl or (lower alkyl),,-thienyl, n is an integer from I to 3, and R is hydrogen or lower alkyl, or pharmaceuticaliy useful acid addition salts thereof.

Most preferred are those compounds of Formula II, wherein each of R and R is hydrogen or methoxy, R is phenyl, tolyl, (methoxy),,-phenyl, (methylenedioxy)- phenyl, (fluoro)-phenyl, (chloro)-phenyl, (trifluoromethyl)-phenyl or thienyl, n is an integer from 1 to 3, and R is hydrogen or alkyl with up to four carbon atoms, or pharmaceutically useful acid addition salts thereof.

The compounds of the invention are prepared according to known methods. For example, the process for their preparation consists in reacting a l-(Z- iminoethylidene)-l ,2,3,4-tetrahydroisoquinol ine of Formula III alk Ph Nii (III) C NH II ri -c-c-R,

with an a-amino-(alkane, cycloalkane or cycloalkene carboxylic or thiocarboxylic acid ester, the nitrile or an acid addition salt thereof and, if desired, converting any resulting compound into another compound of the invention.

Said ester is advantageously a lower alkyl, e.g. the methyl or ethyl, ester or thioester. Depending on the sulfuror nitrogen content of said carboxylic acid derivatives, compounds of Formula I are obtained, wherein X is thio or imino.

The above process is carried out according to standard methods, for example in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/or inert atmospheres, such as nitrogen, at temperatures equal to or advantageously higher than room temperature, at atmospheric or superatmospheric pressure. Condensing agents are either acids or bases, for example, mineral acids, e.g. hydrohalic acids, nitrogen bases or alkalis respectively, preferably tert. amines, such as pyridine, or alkali metal hydroxides or lower alkoxides, e.g. sodium hydroxide, methoxide or ethoxide.

The compounds of the invention so obtained can be converted into each other according to known methods. For example, resulting oxo-compounds can be converted into thio-compounds or vice versa, e.g. by treating the former with sulfur or sulfurization agents, such as phosphorus pentasulfide, or treating the latter with desulfurization agents, such as lead or mercury oxide. Resulting aralkoxy, e.g. benzyloxy compounds can be hydrogenolyzed, for example, with the use of catalytically activated hydrogen, e.g. hydrogen in the presence of palladium catalysts. Resulting phenols can be etherified or esterified, for example, with the use of reactive derivatives of corresponding alcohols or acids, such as lower alkyl halides, sulfates or sulfonates, e.g. methyl or ethyl iodide, sulfate or p-toluenesulfonate; or lower alkanoic acid halides or anhydrides, e.g. acetyl chloride or acetanhydride. Analogously the lower alkyl quaternaries or 5-lower alkylenolethers are obtained by reacting resulting compounds either directly with said derivatives of lower alkanols, or resulting 5-oxo compounds with phosphorus halides or oxyhalides, e.g. phosphorus pentachloride or oxychloride first, and subsequently with alkali metal lower alkoxides or -sulfides, e.g. those mentioned above, or sodium methylor 0thylsulfide, to yield said enol ethers.

The compounds of the invention are obtained in the free form or in the form of their acid addition salts, depending on the conditions under which the process is carried out. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalies or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful acid addition salts. Such acids are inorganic or organic acids, for example, mineral acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid, or aliphatic, alicyclic. araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, aminobenzoic, anthranilic, 4-hydroxyben2oic, salicylic, 4-aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; methionine, tryptophan, lysine or arginine. These or other salts, for example, the picrates, can also be used in the purification of the free compounds. ln view of the close relationship between the salts and the free compounds, whenever such are referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g. by the fractional crystallization of dor l-tartrates.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. Thus, for example, when using acidic condensing agents, which can be reagents also, such as salts, e.g. glycine ethyl ester hydrochloride, the primary condensation product is that of Formula lV wherein R is preferably lower alkyl. Upon treatment with bases (which again can be reagents), said compounds ring-close to those of Formula I. Also, the above phenols can be used in the form of their alkali metal, e.g. sodium salts. Mainly such starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting material used can be prepared by methods known per se, for example, by reacting a l-alkyl- 3,4-dihydroisoquinoline of Formula V (prepared according to the Bischler-Napieralski reaction) with an alkali metal amide, such as a lithium dilower alkylamide, e.g. lithium-diisopropylamide, condensing the resulting metal compound with a reactive functional derivative of the acid R -COOH, such as a lower alkyl ester, iminoester, N-lower alkylated iminoester or the nitrile thereof, and converting any resulting l-(2-oxoethylidene l ,2,3 ,4-tetrahydroisoquinoline into the corresponding imino compound of Formula III, for example, by reacting said carbonyl derivative (vinylogous amide) with a halogenating or esterifying agent, such as a phosphorus halide or oxyhalide, or an acidified lower alkanol, e.g. ethanolic hydrogen chloride, and reacting the resulting vinylogous amidhalide or imino ester with ammonia. Said compounds of Formula III and their oxoprecursors, are not only new and valuable starting materials or intermediates respectively, but also pharmacologically active compounds, which exhibit tranquilizing, muscle relaxing and analgetic effects.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cullulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (0) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, ((1) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving stabilizing wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/0r buffers. Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to percent, preferably about 1 to 50 percent, of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construedas being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 The mixture of 7.3 g of 1-[2-imino-2-(3,4- methylenedioxyphenyl)ethylidene]-1,2,33,4- tetrahydroisoquinoline, 17.5 g of glycine ethyl ester hydrochloride and ml of anhydrous ethanol is refluxed for 3 hours and evaporated under reduced pressure. The residue is taken up in methylene chloride, the solution washed with cold 5 percent aqueous sodium hydroxide, dried and evaporated, to yield the N-[ l-(3,4- methylenedioxyphenyl )-2-( l ,2,3 ,4-tetrahydrol isoquinolylidene]-glycine ethyl ester. It is taken up in 80 ml of anhydrous ethanol, 25 ml of N-ethanolic sodium ethylate are added and the mixture stirred for 16 hours at room temperature. It is evaporated under reduced pressure, the residue taken up in methylene chloride, the solution washed with aqueous sodium bicarbonate, dried, evaporated and the residue chromatographed on 25 g of silica gel. The column is eluted with chloroform, the eluate evaporated and the residue triturated with petrolether, to yield the 2-(3,4- methylenedioxyphenyl )7,8-dihydro[ 1 ,4- ]diazepino[7,l-a]isoquinolin-5(4H)-0ne of the formula NMR (CDCl;,): 8 2.9, 3.9, 4.45, 5.95 and 6.7-7.8

The starting material is prepared as follows: Themixture of 50 g of N-phenethyl-acetamide and 500 g of polyphosphoric acid is stirred at 200205 for 3 hours. It is poured into 2 kg of crushed ice, the solution made basic with 30 percent aqueous sodium hydroxide while cooling and extracted with methylene chloride. The extract is dried, evaporated and the residue taken up in 600 ml of diethyl ether. The solution is cooled with ice, 4 ml of acetyl chloride are slowly added, the mixture stirred for 15 minutes, combined with some crushed ice and washed twice with 250 ml of N hydrochloric acid. The aqueous solution is made basic with 30 percent aqueous sodium hydroxide and extracted with methylene chloride. The extract is dried, evaporated, the residue distilled and the fraction boiling at ll4l l5/l2 mm I-Ig collected, to yield the l-methyl-3,4- dihydroisoquinoline.

The solution of 14.52 g thereof in ml of diethyl ether is added dropwise to the mixture prepared from 14.2 ml of diisopropylamine in 100 ml of diethyl ether and 62 ml of 1.6N butyl lithium in hexane, while stirring at 20 to 30 under nitrogen. After h hour the mixture is cooled to 70 and the solution of 14.7 g of 3,4-methylenedioxybenzonitrile in 120 ml of diethyl ether is added dropwise. After stirring overnight, it is diluted with diethyl ether, washed with water, dried and evaporated. The residue is heated at l25/0.1 mm Hg to remove starting material, and the resulting l-[2 imino-2-( 3 ,4-methylenedioxyphenyl )-e thylidene]- 1,2,3,4-tetrahydroisoquinoline, melting at 105107, used as such.

EXAMPLE 2 The mixture of 6.5 g of l-[2-imino-2-(3,4,5- trimethoxyphenyl )-ethylidene]-6 ,7dimethoxy-1 ,2,3 .4 tetrahydroisoquinoline, l 1.4 g of glycine ethyl ester hydrochloride and 50 ml anhydrous ethanol is refluxed for 2 hours and evaporated under reduced pressure. The residue is taken up in methylene chloride, the solution washed with cold 5 percent aqueous sodium hydroxide, dried and evaporated. The residue is taken up in diethyl ether, the solution clarified with charcoal, filtered and evaporated, to yield the N-[ 1-(3,4,5- tnimethoxyphenyl)-2-(6,7-dimethoxy-1,2,3,4- tetrahydro-l -isoquinolylidene)-ethylidene}-glycine ethyl ester, melting at l38140. It is taken up in 80 ml of anhydrous ethanol, the solution combined with 13.5 ml of 1.1 N methanolic sodium methylate and the mixture stirred for 16 hours at room temperature. it is evaporated under reduced pressure, the residue taken up in methylene chloride, the solution washed with aqueous sodium bicarbonate, dried, evaporated and the residue recrystallized from ethanoldiethyl ether, to yield the 2-( 3 ,4,5-trimethoxyphenyl I 0,1 1- dimethoxy-7,8-dihydro[ l ,4]diazepino]7,1- a]isoquinolin-5(4H)-one, melting at 214-215. The hydrochloride thereof is obtained from a concentrated ethanolic solution of the base, which is acidified with ethanolic hydrogen chloride; it melts at 237 2382 The starting material is prepared as follows: To the stirred mixture of 53.7 g of 3,4-dimethoxyphenethylamine, 700 ml of methylene chloride and 50 ml of triethylamine, the solution of 23.4 g of acetyl chloride in 500 ml of methylene chloride is added dropwise. After stirring the mixture for 2 hours, water and sodium carbonate is added, the organic layer separated, dried and evaporated, to yield the N-3,4-dimethoxyphenethylacetamide, melting at 9697.

43 g thereof are dissolved in 1.45 lt of a chloroformdiethyl ether solution, containing 300 mg polyphosphoric acid ethyl ester per ml and the mixture is evaporated under reduced pressure. The residue is stirred at l20-125 for 70 minutes, cooled and combined with crushed ice. The solution obtained is washed with ethyl acetate, adjusted with 30 percent aqueous sodium hydroxide to pH 10 and extracted with chloroform. The extract is dried, evaporated and the residue recrystallized from diethyl ether, to yield the 1-methyl-6,7- dimethoxy-3,4-dihydroisoquinoline melting at 101102.

The solution of 5.12 g thereof in ml of tetrahydrofuran is added dropwise to the mixture prepared from 3.55 ml of diisopropylamine in 25 mi of diethyl ether and 15.5 ml of 1.6N butyl lithium in hexane under nitrogen at After completed addition the mixture is stirred and allowed to warm up to room temperature. Thereupon, it is cooled to 70 and combined with the solution of 4.83 g of 3,4,5-trimethoxybenzonitrile in 25 ml of tetrahydrofuran. The mixture is allowed to warm up to room temperature and stirred overnight. lt is then cooled to 0, water and diethyl ether are added and the organic layer separated. The aqueous solution is extracted with diethyl ether, the combined organic solutions dried, evaporated and the residue recrystallized from diethyl ether, to yield the l-[2-imino-2 (3,4.5- trimethoxyphenyl)-ethylidene]'tiJ-dimethoxy-1,23,4- tetrahydroisoquinoline melting at l42144.

The hydrochloride thereof, prepared from its con centrated ethanolic solution by neutralization with ethereal hydrogen chloride. melts at 239240.

By replacing in the above procedure the 3.4,5 trirnethoxybenzonitrile by the equivalent amount of methyl 3,4,5-trimethoxybenzoate, the tetrahydrofuran by three times the volume of diethyl ether and the water by 2N hydrochloric acid to reach the pH =4, the l-[ 2- oxo-2-( 3,4,5-trimethoxyphenyl )-ethylidene l-hfidimethoxy-l,2,3,4-tetrahydroisoquinoline is obtained melting at l l4l 15. (It can also be obtained by hydrolysing 15 g of the former imino compound in 330 ml of methylene chloride with 150 ml of N hydrochloric acid at room temperature for 2 hours while stirring. The pH of the mixture is adjusted to 8 with sodium hydroxide and carbonate. the organic solution separated. dried, evaporated and the residue recrystallized from diethyl ether.)

The mixture of 0.8 g thereof. 10 ml of toluene and 0.43 g of phosphorus pentachloride is heated to 1 10 for 7'2 hour and evaporated under reduced pressure, to yield the corresponding vinylogous amidchloride. It is taken up in 30 ml of methylene chloride saturated with ammonia and the mixture stirred for 2 days at room temperature. It is washed with 0.1N aqueous sodium hydroxide, dried and evaporated, to yield the l-[2- imino-2-( 3,4,5-trimethoxyphenyl )ethylidene 141,1 dimethoxy-l ,2,3,4-tetrahydroisoquinoline.

The same compound is obtained by stirring 1.2 g of the vinylogous amide with 30 ml of saturated ethanolic hydrogen chloride for 2 days at room temperature. evaporating the mixture and stirring the residual vinylogous imino-ethyl ester with 30 ml of methylene chloride-ammonia for 3 days and working up the mixture as described above.

EXAMPLE 3 The mixture of 4.2 g of l-[2-imino-2-(3,4- methylenedioxyphenyl)-ethylidene]6,7-dimethoxy l,2,3,4-tetrahydroisoquinoline, 8.4 g of glycine ethyl ester hydrochloride and 82 ml of anhydrous ethanol is refluxed for 1 Be hours and evaporated under reduced pressure. The residue is taken up in chloroform, the solution washed with ice cold 5 percent aqueous sodium hydroxide, dried and evaporated, to yield the N[ (3,4-methylenedioxyphenyl)-2-(6,7dimethoxy- 1,2,3 ,4-tetrahydrol -isoquinolylidene )-ethylidene glycine ethyl ester. It is taken up in 60 ml of anhydrous ethanol, 13.2 ml of N-ethanolic sodium ethylate are added and the mixture stirred for 16 hours at room temperature. It is evaporated under reduced pressure, the residue taken up in chloroform, the solution washed with aqueous sodium bicarbonate, dried, evaporated and the residue recrystallized from ethanol, to yield the 2-(3,4-methylenedioxyphenyl)-10,l ldimethoxy-7,8-dihydro[ 1,4 ]diazepino[ 7 l a]isoquinolin-5(4H)-one, melting at 2l4215; the hydrochloride thereof melts at 188 l (ethanol).

The starting material is prepared as follows: To the solution of 10.7 ml of diisopropylamine in 75 ml of diethyl ether, 47 m1 of 1.6 N butyl lithium in hexane are added while stirring at -20 under nitrogen. Thereupon the solution of 15.5 g of 1-methyl-6,7-dimethoxy-3,4- dihydroisoquinoline in 100 ml of tetrahydrofuran is added while stirring at -45. After completed addition, the mixture is stirred and allowed to warm up to room temperature, whereupon it is cooled to 70 and combined with the solution of 11.1 g of 3,4-methylenedioxybenzonitrile in 75 ml of tetrahydrofuran. The mixture is allowed to warm up to room temperature and stirred for 16 hours. It is combined with crushed ice, the organic layer separated and the aqueous solution extracted with methylene chloride. The combined organic solutions are dried, evaporated and the residue recrystallized from diethyl ether, to yield the 1[2- imino-2-(3,4-methylenedioxyphenyl)-ethylidene]-6,7- dimethoxy-l,2,3,4-tetrahydroisoquinoline, melting at 175l76.

EXAMPLE 4 3.5 g of 1-[2-imino-2-(3,4-methylenedioxyphenyl)- ]diazepino[7,l-a]isoquinolin-5(4H)-one hydrochloride, melting at l84l87.

EXAMPLE6 The mixture of 5.07 g of l-l2-imino-2-(3,4-

methylenedioxyphenyl )-ethylidene]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline, 7.9 g of d,l-valine ethyl ester hydrochloride and 72 ml of pyridine is refluxed for 44 hours under nitrogen and evaporated under reduced pressure. The residue is taken up in methylene chloride, the solution washed with aqueous sodium bicarbonate, dried and evaporated. The residue is'chromatographed on 50 g of silica gel and eluated with chloroform. The eluate is evaporated, the residue taken up in 500 ml of 5 percent hydrochloric acid and the so- 1 ethy ldenei lmthoxy lutron washed with benzene-ethyl acetate (1:1). It 1s tetrahydrolsoqurnolrne, 7.7 g of d,l-alan1ne ethyl ester made bas1c w1th aqueous sod1um hydroxlde, extracted hydrochlorlde and ml of anhydrous ethanol is re- I H d f 12 h d t d d d d with methylene chlorrde, the extract drred and evapouxe or oilrs evapora.e un re uce rated. The residue is taken up in acetone and the solu- Rressureresldue up m methy ene ch10 30 tion neutralized with ethereal hydrogen chloride, to rlde, the solutlon washed w1th 1ce cold 5 percent aqueyield the d,1 2 (3,4 methylenedioxyphenyl ous sodrum hydroxrde, dried and evaporated. The resriSOprOpyHOJ 1 dimethOxy -/,8 due 1s trlturated wrth methylene chlorlde, to y1eld Resrdihydro[1Aldiazepinow,1 a]isoquinolin 5(4H) one due A and the mother liquor is combined with 60 ml of hydrochloride melting at 1 9 193 ethanol and 9 ml of 1.1 N methanolic sodium methylate and stirred for 16 hours at room temperature. It is EXAMPLE 7 evaporated under reduced pressure, the residue com- Analogous to the method illustrated by the Examples bined with Residue A and dissolved in methylene chlol to 4, the following compounds of Formula 11 are preride. The solution is washed with aqueous sodium bipared from equivalent amounts of the corresponding carbonate, dried, evaporated and recrystallized from Starting material of Formula 11 H1 m.p.C recrysl. m.p.(. n1.p.C No. R5 R,; R7 base from HCl(A) start Ill 1 oCH OCH C l-l 104-106 A B 162-164 14o-147 2 do. do. 44 0,11, 156-157 A B 151-152 1146-111X 3 dov do. 4-Cl-C H, 196 A a 175-176 177-1711 4 do. do. 4-CH O-C H, 174-175 A 168-170 149-151 5 do. do. 3,4 c11,o .,1r, 98-99 A B 131-132 196-197 6 do. do. Z-thienyl 183-185 A B 194-195 144-145 7 o-cH -0 31,4cr1 o,-c,1-1 183-185 A a 270-271 107-109 A ethanol, 8 dicthyl ether methanol, to yield the d,l-2-(3,4- EXAMPLE 8 methylenedioxyphenyl)-4-methyl-10,1 l-dimethoxy- 7,8-dihydro[1,4]diazepino[7,1-a]isoquinolin- 5(4H)-one, melting at l38l40. The hydrochloride thereof melts at 18018 1 (ethanol).

EXAMPLE 5 Preparation of 10,000 tablets each containing 100.0 mg of the active ingredient:

Formula:

2-(3,4-methylenedioxyphenyl)-10,1 1- dimethoxy-7,8-dihydro[ 1,4]diazepino [7,1-a]isoluinolin-5(4H)-one hydrochloride 1,000.00 g

Lactose 2,535.00 g Corn starch 125.00 g Polyethylene glycol 6,000 15000 g Talcum powder 150.00 g Magnesium stearate 40.00 g Purified water q.s.

Procedure:

All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose,

talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 10.3 mm diameter, upper bisected.

Analogously, tablets are prepared containing the same amount of any of the other compounds described in the previous examples.

EXAMPLE 9 The mixture of 3.26 g of methylenedioxyphenyl)-10,1 ldimethoxy-7,8- dihydro[ l ,4]diazepino[7,l-a]isoquinolin-(4H)-one, 1.85 g of phosphorus pentasulfide and 85 ml of pyridine is refluxed under nitrogen for 1 hour and evapo rated under reduced pressure. The residue is taken up in methylene chloride, the solution washed with aqueous sodium bicarbonate, dried and evaporated. The residue is chromatographed on 23 g of silica gel and the column eluted with chloroform. The eluate is evaporated and the 2.4 g of residue crystallized from methylene chloride-diethyl ether, to yield the 2-(3,4- methylenedioxypheny] l 0,] l-dimethoxy-7,8- dihydro[ 1 ,4]diazepino[7, 1 -a]isoquinolin-5(4H)- thione melting at l82-l 84, its hydrochloride melts at 223226 (ethanol).

I claim:

1. A compound corresponding to the formula wherein each of R and R is hydrogen, methyl, methoxy, or both R and R are methylenedioxy, R is phenyl, (methyl),,-phenyl, (methoxy),,phenyl, (methylenedioxy)-phenyl, (fluoro or chlorolyrphenyl, (trifluoromethyl)-phenyl, thienyl or (methyll thienyl, n is an integer from 1 to 3. and R is hydrogen or alkyl with up to four carbon atoms, or pharmaceutically useful acid addition salts thereof.

2. A compound as claimed in claim I, in which formula each of R and R is hydrogen or methoxy. R is phenyl, 3,4,5-(methoxyi -phenyl, 3,4-(methylcncdioxy)-phenyl, 4-(fluoro)-phenyl, 4-(chloro)-phenyl. or 2 thienyl, n is an integer from 1 to 3, and R is hydrogen or alkyl with up to three carbon atoms, or pharmaceutically useful acid addition salts thereof.

3. A compound as claimed in claim 1 and being the 2-(3,4-methylenedioxyphenyl)-lO,l l-dimethoxy-7,8- dihydr0[ l,4]diazepino[ 7, l -a]isoquinolin-5(4H)-one, or a pharmaceutically useful acid addition salt thereof.

4. A compound as claimed in claim 1 and being the d,l-2-(3,4-methylenedioxyphenyl)-4-methyll0,l l- 'dimethoxy-7,8-dihydro[ l ,4 ]diazepin0[ 7, l a]isoquinolin-5(4H)-one or a pharmaceutically useful acid addition salt thereof. 

1. A COMPOUND CORRESPONDING TO THE FORMULA
 2. A compound as claimed in claim 1, in which formula each of R5 and R6 is hydrogen or methoxy, R7 is phenyl, 3,4,5-(methoxy)n-phenyl, 3,4-(methylenedioxy)-phenyl, 4-(fluoro)-phenyl, 4-(chloro)-phenyl, or 2-thienyl, n is an integer from 1 to 3, and R8 is hydrogen or alkyl with up to three carbon atoms, or pharmaceutically useful acid addition salts thereof.
 3. A compound as claimed in claim 1 and being the 2-(3,4-methylenedioxyphenyl)-10,11-dimethoxy-7,8-dihydro(1,4)diazepino( 7,1-a)isoquinolin-5(4H)-one, or a pharmaceutically useful acid addition salt thereof.
 4. A compound as claimed in claim 1 and being the d,l-2-(3,4-methylenedioxyphenyl)-4-methyl-10,11-dimethoxy-7,8-dihydro( 1, 4)diazepino(7,1-a)isoquinolin-5(4H)-one or a pharmaceutically useful acid addition salt thereof. 